DE2707095B2 - - Google Patents

Description

15th

The invention relates to 2-isopropylaminopyrimidine orthophosphate The invention also relates to the use of this salt in combating Neuropathies with different causes.

The salt according to the invention has the formula: example

6 liters of ethanol and 685 g (5 mol) of 2-isopropylaminopyrimidine are placed in a 10 liter reactor and stirred. The solution is mixed with 600 g (5.2 mol) Phosphoric acid and the mixture obtained is refluxed for 1 hour. You get a dark green one Solution which is treated with 30 g of charcoal. After the charcoal has been separated off, the product becomes overnight Allowed to crystallize with stirring, separated, with Washed out ethanol and dried at 50 ° C. This gives 1.027 g (yield 87%) of a white powder of m.p. 125 ° C. Analysis of the compound shows good agreement with the formula C7H14O4N3P.

toxicity

The acute toxicity of the compound according to the invention against mice is determined when intraperitoneally or oral administration. The table below shows the results and the corresponding ones Values for the 2-isopropylarninopyrimidinedichloroacetate known from DE-AS 2249425, which is based on effectiveness in the same therapeutic area

H-C

H-C

\
N N CH ₃ H ₃ PO ₄ shows 30th Intraperitoneal Dichloro Ortho- Il /
C-NH-CH administration acetate phosphate H ■■ <■: * ■
I. / \ Oral administration LD ₅₀ , LD ₅₀ , I. CH, g / kg g / kg C. 0.630 1.530 1,700 2.830

35

or the molecular formula C7H14O4N3P (molecular weight 235.17).

The salt is a white, crystalline powder that is used in 125 ° C melts and is soluble in water

According to the invention, the salt is produced by reacting 2-isopropylaminopyrimidine with phosphoric acid manufactured; the reaction is conveniently carried out in the presence of a solvent such as a lower one Alcohol.

The following example is intended to explain the production of the compound according to the invention in more detail.

The compound according to the invention thus has a significantly lower toxicity than the known one Connection on.

A comparison of the subacute toxicities of both compounds with rats confirms the lower level Toxicity and better tolerability of the salt according to the invention.

At similar doses, there will be the following differences between the modes of action of the two salts (each test is carried out on 10 rough surfaces; in the comparison tests, 10 Rats used):

treatment

Weight loss
on the 37th day compared to
Comparative values,

Number of am
end of
treatment
perished animals

Oral administration of the dichloroacetate to 23.1

6 days a week for 5 weeks
at a dose of 570 mg / kg

Oral administration of the orthophosphate to 7.3

7 days a week for 6 weeks
at a dose of 600 mg / kg

When the dichloroacetate is administered, a 40 to 45% liver enlargement (Hepatomega-He) found, while this is not the case with the administration of the orthophosphate according to the invention

65

pharmacology

The following comparative experiment shows the pharmacological effect of the compound according to the invention,

ύί 095

which relates to the regeneration of the sciatic nerve in adult male Wistar rats

The sciatic nerve of the rats is taught with the aid of a 20 minutes at -20 ⁰ C applied thermal probe, a lesion is then administered to the rats intraperitoneally for a predetermined period, the comparative compounds and the inventive compound. After the treatment, the rats are sacrificed.The sciatic nerve is isolated and brought into contact with a series of 70 thin, parallel platinum wires (spaced 1 mm apart) The reception of an electrical signal transmitted above the lesion site is examined on the platinum wires. at which the signal can be received gives the regenerated length.

At least five rats are used for each substance tested and each duration of treatment

Four substances are tested for intraperitoneal administration: the free base 2-isopropyIami nopyrimidine (87 mg / kg), its dichloroacetate (170 mg / kg, corresponding to 87 mg / kg of the base), its orthophosphate (145 mg / kg, corresponding to 87 mg / kg) mg / kg of the base) and a mixture of vitamins Bi (500 mg / kg), B ₂ (500 mg / kg) and Be (5 mg / kg), which is known to be the most effective agent in the relevant field showed that the effect when using 2-isopropylaminopyrimidine salts depends mainly on the amount of base actually contained in the salts, with each salt bringing only a slight change in terms of the base. The doses for the dichloroacetate and the orthophosphate were therefore given as equivalents for the dose the base of 87 mg / kg

ίο calculated. The comparison with the base is purely theoretical, since the base does not allow therapeutic administration due to its too high pH value.
The test results can be seen from the table below, which also shows the values obtained in comparison animals (five groups of test animals with a treatment duration of 7, 11, 14, 17 and 21 days), m stands for the length of the regenerated nerve (in the form of the Mean value of the lengths measured for the η ι- 20 test animals of the group). If no number appears (for a treatment period of 17 or 21 days), this means that the regenerated length exceeds the length of the sample taken

Treatment duration (days)
11 14

21

Comparative samples m (mm)
η 5
5 10.6
5 13.2
5 21.8
5 26.8
5 Free base, 87 mg / kg m
η 6.3
5 13.8
6th 25.1
6th - _ Dichloroacetate, 170 mg / kg
(corresponds to 87 mg / kg
free base) m
η 6.5
6th 14.5
6th 21.1
6th Orthophosphate, 145 mg / kg
(corresponds to 87 mg / kg
free base) m
η 6.7
7th 16.2
5 22.7
7th Vitamin B ₁ , B ₆ , B ₁₂ m
η 9.4
5 13.2
5 16.2
5 21.4
5 25.5
5

Formulation and dosiology

The salt of the invention can be in any therapeutically suitable form, e.g. B. in tablets or gelatin capsules, which contain 50 mg of the salt per single dosage form together with a binder or carrier (such as lactose) are provided. For injection preparations, the salt can be filled in doses into ampoules, into which at least 10 mg of the active ingredient dissolved in water are incorporated. As for the dosage in human medicine, oral administration requires a daily dose of 250 mg to 2 g, whereas injection preparations can be administered in daily doses of 10 to 40 mg.
An example of a tablet formulation is the following:

2-isopropylaminopyrimidine orthophosphate 250 mg ₅₀ microcrystalline cellulose 170 mg Cornstarch 115 mg Talk 47 mg Silica 6 mg Hydrogenated castor oil 5 mg _S5 magnesium stearate 7 mg

600 mg

Claims (3)

Patent claims: 1,2-isopropylaminopyrimidine orthophosphate 2. Process for the preparation of the compound according to claim 1, characterized in that one 2-Isopropylaminopyrimidine in the presence of a suitable polar solvent with a slight excess of orthophosphoric acid brings to implementation 3. Use of the compound of claim 1 in combating neuropathies. 10